The present invention is directed to pharmaceutical compositions for transmucosal delivery of biologically active agents. More particularly, this invention relates to a novel method for controlling and promoting the rate and extent of transmucosal permeation and absorption of an anticonvulsive agent by coadministration of the medicament with a pharmaceutically acceptable co-solvent system comprising an aliphatic alcohol, a glycol, and water, and their combinations with a biological surfactant such as a bile salt or a lecithin. Even more particularly, this invention relates to the pharmaceutical compositions to provide a patient-acceptable transnasal anticonvulsive delivery system, which may be useful for the emergency management of status epilepticus and fever seizures in a prompt and convenient manner of administration.
Status epilepticus is a neurological emergency in which mortality ranges from 3-35%. The major goal of treatment is rapid management of pathological seizure activity; the longer that the episode of status epilepticus is untreated, the more difficult it is to control and the greater the risk of permanent brain damage. Thus, critical to the management of the patient is a clear plan, involving prompt treatment with effective drugs in adequate doses having a proper pharmaceutical formulation as well as attention to hypoventilation and hypotension.
Currently several drug regimens have been proven to be applicable in treating status epilepticus. Diazepam and lorazepam are the most widely used benzodiazepines for this purpose. Intravenous administration of anticonvulsants is the most rapid way to suppress epileptic convulsions. However, other routes of administration may be highly desirable when intravenous administration is inconvenient and delaying, for instance, because of technical difficulties such as requirements for sterile equipment and skilled personnel, and because of the possible development of thrombophlebitis. In addition, intravenous medication is often associated with hypotension, cardiac dysrhythmia or central nervous system depression. In this regard Moolenaar [Moolenaar et al., Int. J Pharm., 5: 127-137 (1986)] attempted to administer diazepain in humans via several other routes such as intramuscular injection, oral tablet and rectal solution. Only the rectal administration was found to provide a fairly rapid absorption and thus, it might be looked upon as an alternative route to IV injection. However, the rectal route is a very inconvenient way of drug administration particularly in emergency treatment. In U.S. Pat. No. 4,863,720 of Burghardt, a sublingual sprayable pharmaceutical preparation is disclosed, in which the active drug can be a benzodiazepine, optimally comprising polyethylene glycol (PEG) and requiring ethanol, di- and/or triglyceride of fatty acids and a pharmaceutically acceptable propellant gas.
More recently, it appears that the mucosal membrane of the nose offers a practical route of administration for therapeutic effect of many medicinal substances. Intranasal administration has the advantages that drugs may be administered readily and simply to achieve a systemic or localized effect, as required. However, the major problem associated with intranasal drug administration is the fact that most drug molecules diffuse poorly and slowly through the nasal mucosal membrane and thus the desired levels of the therapeutic agent cannot be achieved by means of simple transnasal administration. An additional constraint concerning nasal administration is that a small administration volume is needed; it is not generally possible to administer more than approximately 150 xcexcl per nostril; above this, the formulation will be drained out into the pharynx and swallowed. Therefore, a great need exists for solvent vehicles, in which the solubility of the drug is high and which, on the other hand, are non-irritating to the nasal mucosa. The intranasal absorption of drugs can be increased by coadministering a chemical adjuvant or permeation enhancers. For example, Lau and Slattery [Lau et al., Int. J Pharm., 54: 171-174 (1989)] attempted to administer a benzodiazepine such as diazepam and lorazepam by dissolving these medicaments in a variety of solvents; triacetin, dimethylsulfoxide, PEG 400, Cremophor EL, Lipal-9-LA, isopropyl adipate and Azone. While many of the solvents dissolved diazepam and lorazepam in the desired concentrations, they were too irritable to be used when administered to the nose. Cremophor EL was found to be the least irritating for nasal mucosal tissue, but the nasal absorption in the use of this vehicle in humans was rather slow (Tmaxxe2x89xa11.4 hours) and the peak concentration was low relative to that observed after IV administration. In U.S. Pat. No. 4,950,664 Rugby described the nasal administration of a benzodiazepine hypnotic in a pharmaceutically acceptable nasal carrier. The carrier may be an aqueous saline solution, an alcohol, a glycol, a glycol ether or mixtures thereof. The results of pharmacokinetic studies in dogs showed that the time to maximum plasma concentration for triazolam was achieved at 18 minutes after the nasal administration, while an effective treatment within 5 minutes is considered to be an attractive goal. Bechgaard and Hjortkjer [Bechgaard et al., J Pharm. Pharmacol., 49: 747-750 (1997)] described the use of pure organic solvents such as glycofurol and tetraethyleneglycol, and their combinations as carriers for nasal delivery of diazepam. The absolute bioavailability, measured during the first 30 minutes after the nasal administration, was 49-62% for the most promising carrier systems examined. In PCT WO 95/31217, Dumex described the use of a pharmaceutical emulsion preparation based on tocopherol and its derivatives for intranasal administration of biologically active compounds including benzodiazepines.
The present invention is a novel method of vehicle modulated administration of an anticonvulsive agent to the mucous membranes of humans and animals. The vehicle system is an aqueous pharmaceutical carrier comprising an aliphatic alcohol or a glycol and their combinations with a biological surfactant such as a bile salt or a lecithin.
An objective of the present invention is to provide a pharmaceutically acceptable carrier system which is capable of enhancing the transmucosal permeation and absorption of an anticonvulsive agent. The ingredients used in the pharmaceutical composition are preferably those of GRAS materials (generally recognized as safe), so there are no major toxicity issues of concern. Another objective of the present invention is to provide a method of controlling the transmucosal delivery of an anticonvulsant at an appropriately adjusted rate so as to achieve an optimum therapeutic effect, while avoiding or reducing adverse side effects. Such compositions are particularly suitable for intranasal administration of the medicaments in the acute treatment of status epilepticus and fever seizures.